Comments on the history of medical-biological studies of aging, the birth of scientific gerontology.

Recent books (Immunity. How Elie Metchnikoff changed the course of modern medicine and Expectations of Life) reviewed the important contribution of Metchnikoff to the emergence of gerontology as a new branch of biomedical sciences. Here, we insist on Metchnikoff's contribution and pivotal role in the emergence of nutrition as a science and its importance for health and longevity. The discovery of phagocytosis by Metchnikoff and of its evolutionary ancestry are at the origin of the emergence of cellular immunity as an independent science besides humoral immunity. The longevity of Metchnikoff (71years) at a time when average life expectancy of men did hardly pass 50years certainly contributed to the acceptance of his teachings. The recent increase of the senior population in most advanced countries is a good opportunity to review the contributions of nutrition to longevity.

Longevity and aging. Mechanisms and perspectives.

Longevity can mostly be determined with relative accuracy from birth and death registers when available. Aging is a multifactorial process, much more difficult to quantitate. Every measurable physiological function declines with specific speeds over a wide range. The mechanisms involved are also different, genetic factors are of importance for longevity determinations. The best-known genes involved are the Sirtuins, active at the genetic and epigenetic level. Aging is multifactorial, not "coded" in the genome. There are, however, a number of well-studied physical and biological parameters involved in aging, which can be determined and quantitated. We shall try to identify parameters affecting longevity as well as aging and suggest some reasonable predictions for the future.

Stress in biology and medicine, role in aging.

In this review, we present a short description of the history of stress in the medical literature followed by a recapitulation of its mechanisms, from the cellular to the organismal level and its role in aging. The medical importance of stress was first taken up as a subject of experimental medicine by physiologists, starting from Claude Bernard's concept of the stability of the "milieu intérieur", altered by stress, followed by others, culminating recently by the elucidation of its mechanisms at the cellular and molecular level. These studies showed that oxidative stress is one of the most important and most frequent form of biological aggression. Its accumulation over time is important for the burnout syndrome and for neuronal aging. There is however a positive side to it also, redox signaling plays an important role in the functional coordination of cellular activities. These mechanisms, still to be more completely evaluated, have to be taken in account for planning efficient protective therapeutic interventions.

Longevity and aging: role of genes and of the extracellular matrix.

Longevity is different for every animal species as well as their genome, suggesting a correlation between genes and life-span. Estimates put the genetic effect from 5 to 35% approximately, suggesting that even genetic effects are dependent on environmental conditions. This contention is largely confirmed by the study of identical twins raised apart. They do not die at the same age and also for different reasons. Aging is not "genetically programmed", it is outside evolutionary constraint. Evolution favors early and efficient reproduction, but does not care for longevity. A number of mechanisms were shown to be involved in the age-dependent decline of vital functions, among them the Maillard reaction (non-enzymatic glycosylation) and the age-dependent upregulation of proteolytic activity. Aging of ECM is a complex process, comprising progressive modification of its macromolecular components and of cell-matrix interactions. An important process is the uncoupling with age of the elastin-receptor from its "young" transmission pathway loosing all physiological effects, but enhancing free radical and elastase release. These processes contribute to age-related ECM degradation, production of matrikins (ECM degradation products with biological activity) aggravating functional loss with age. Both genetic and post-genetic mechanisms are susceptible to be influenced by medical, pharmacological and dietary interventions. Among the genetic mechanisms, those attributed to Sirtuins (7 orthologs identified in the human genome) are especially important. Among the environmental effects, nutrition, hygiene and weather conditions play a role. These data justify some predictions on the evolution of life expectancy taking in account also socio-economic factors. Biological constraints become evident by the comparison of centenarians and supercentenarians (less than 1% of the centenarians) putting an upper limit to the attainable human lifespan.

Circulating elastin peptides, role in vascular pathology.

The atherosclerotic process starts with the degradation of elastic fibers. Their presence was demonstrated in the circulation as well as several of their biological properties elucidated. We described years ago a procedure to obtain large elastin peptides by organo-alkaline hydrolysis, κ-elastin. This method enabled also the preparation of specific antibodies used to determine elastin peptides, as well as anti-elastin antibodies in body fluids and tissue extracts. Elastin peptides were determined in a large number of human blood samples. Studies were carried out to explore their pharmacological properties. Similar recent studies by other laboratories confirmed our findings and arose new interest in circulating elastin peptides for their biological activities. This recent trend justified the publication of a review of the biological and pathological activities of elastin peptides demonstrated during our previous studies, subject of this article.

Aging of connective tissues: experimental facts and theoretical considerations.

In this chapter, we describe in detail the age-dependent modifications of connective tissues, separately for their cellular and extracellular compartments. Cell aging was studied by the in vitro method established by Hayflick as well as by ex vivo explant cultures, and results with both methods are discussed. Follows then the description of age changes of macromolecular components of extracellular matrix as well as the decline with age of receptor-mediated cell-matrix interactions. These interactions mediated by several types of receptors, as integrins, the elastin receptor and others, play a crucial role for the definition and regulation of the differentiated cell phenotype. Age-related modifications of both matrix components and receptors are discussed in order to explain the mechanisms of the age-dependent modulations of cell-matrix interactions. Finally, we discuss the relations between age changes of matrix components and the onset of age-related diseases, especially cardiovascular pathologies mostly involved in age-dependence of functions and limitation of longevity.

Longevity and aging. Role of free radicals and xanthine oxidase. A review.

Longevity and aging are differently regulated. Longevity has an important part of genetic determinants, aging is essentially post-genetic. Among the genes involved in longevity determination, sirtuins, activated also by calorie restriction and some others as the TOR pathway, attracted special interest after the insulin­IGF pathway first shown to regulate longevity in model organisms. For most of these genes, postponement of life-threatening diseases is the basis of their action which never exceeds about 35% of all determinants, in humans. Among the post-genetic mechanisms responsible for age-related decline of function, free radicals attracted early interest as well as the Maillard reaction, generating also free radicals. Most attempts to remediate to free radical damage failed however, although different scavenger mechanisms and protective substances are present in the organism. Synthetic protectors were also tested without success. The only example of a successful treatment of a free radical mediated pathology is the case of xanthine oxidase, involved in cardiovascular pathology, essentially during the ischemia-reperfusion process. Its inhibition by allopurinol is currently used to fight this deadly syndrome.

Fifty years of structural glycoproteins.

During decades preceding and following the last war, a favourite subject of biochemists was to study glycoproteins. One class of these substances, found in connective tissues were characterised as polysaccharides, most of them found to be linked to proteins, designated later as glycosaminoglycans and proteoglycans. Another family of glycoconjugates represented epithelial mucins as found in the gastro-intestinal and respiratory tracts and conduits. A third family of glycoconjugates is represented by circulating glycoproteins isolated from the blood plasma, mostly studied by medical biochemists in relation to pathological conditions comprising those increasing during the inflammatory reaction: acute phase glycoproteins. Their study suggested that they might be derived from connective tissues. Although inflammatory glycoproteins derive mostly from the liver, the possibility of connective tissue origin of glycoproteins remained open. Using cornea, an avascular tissue, we could show that connective tissues also synthesize glycoproteins. We proposed to designate them "structural glycoproteins" (SGP-s) to distinguish them from circulating, blood-born glycoproteins coming from the liver. They play locally "structural" roles in connective tissues where they are synthesized. Soon after fibronectin was identified and shown to mediate cell-matrix interactions. A large family of glycoproteins were then isolated from a variety of sources, cells, tissues others than liver, confirming our original hypothesis. The first experiments on these glycoproteins were published from 1961/1962 giving the opportunity to recapitulate this biochemical adventure 50 years later, together with the celebration of the foundation of the first connective tissue society in Europe, as described in the first article in this issue.

Celebration of the 50th anniversary of the foundation of the French society for connective tissue research. Its short history in the frame of the origin and development of this discipline.

The science of connective tissues has (at least) a double origin. Collagen, their major constituent was first studied in conjunction with the leather industry. Acid mucopolysaccharides (now glycosaminoglycans) were characterised by (bio)-chemists interested in glycoconjugates. They joined mainly hospital-based rheumatology departments. Later started the study of elastin with the discovery of elastases and of connective tissue-born (structural) glycoproteins. Besides rhumatologists and leather-chemists mainly pathologists became involved in this type of research, followed closely by ophthalmology research. The first important meetings of these diverse specialists were organised under the auspices of NATO, first in Saint-Andrew's in GB in 1964 and a few years later (1969) in Santa Margareta, Italy. With the discovery of fibronectin, a "structural glycoprotein", started the study of cell-matrix interactions, reinforced by the identification of cell-receptors mediating them and the "cross-talk" between cells and matrix constituents. The first initiative to organise societies for this rapidly growing discipline was that of Ward Pigman in New York in 1961, restricted however to glycol-conjugates. Next year, in 1962 was founded the first European Connective Tissue Society in Paris: the "Club français du tissu conjonctif", which played a crucial role in the establishment of schools, laboratories, national and international meetings in the major cities of France: Paris, Lyon, Reims, Caen,Toulouse. A second European society was born in Great Britain, and at a joint meeting with the French society at the Paris Pasteur Institute, was founded in 1967 by these societies the Federation of European Connective Tissue Societies (FECTS). Their meetings, organised every second year, drained a wide attendance from all over the world. An increasing number of young scientists joined since then this branch of biomedical discipline with several international journals devoted to connective tissue research, to matrix biology. The increasing number and quality of the young generation of scientists engaged in research related to the extracellular matrix or better Biomatrix and cell-matrix interactions is a further guarantee for the continued interest in this crucial field of science at the interface of basic and medically oriented research.

Cell-Matrix interactions, the role of fibronectin and integrins. A survey.

In this review, we present several aspects of cell-matrix interactions, especially the role of fibronectin and integrins in the mediation of these interactions. As this field of investigations literally exploded over the last decades, we had to limit this review to some aspects of this field. We cited experiments giving details on the modifications of fibronectin molecules during their interactions with cells as well as on recent progress of the molecular mechanisms of fibronectin-integrin interactions. We insisted on the molecular details which were shown to play a role in the bi-directional signals "sent" by cells to the surrounding matrix (inside-out and outside-in). A number of recent publications confirmed the physiopathological importance of these messages both for the normal function of tissues as well as for the understanding of their pathological modifications. We insist also on the importance of fibronectin-fragments during some pathologies.

Physiology of skin aging.

Skin is the most voluminous organ of the body. It assumes several important physiological functions and represents also a "social interface" between an individual and other members of society. This is the main reason its age-dependent modifications are in the forefront of dermatological research and of the "anti-aging" cosmetic industry. Here we concentrate on some aspects only of skin aging, as far as the cellular and extracellular matrix components of skin are concerned. Most well studied mechanisms of skin aging can be situated at the postgenetic level, both epigenetic and post-translational mechanisms being involved. Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.

The Maillard reaction--illicite (bio)chemistry in tissues and food.

We present a review of our early work on the Maillard reaction, at the interface of food chemistry and tissue biochemistry, as well as the reinterpretation of our early findings in the light of recent advances in the chemistry of the involved reactions. These concern specifically the role of lower aldehydes, produced during the glycolytic pathways and especially acetaldehyde. We also review some of our recent findings on the cytotoxic and genotoxic aspect of these "illicit" organic reactions, taking place in tissues (and also in food products) besides the genetically "programmed" metabolic pathways. Some recent results in organic-pharmaceutical chemistry confirm the potential importance of the reviewed reactions both in food chemistry and in tissues as well as the pathological importance of reactions taking place in tissues.

[The connective tissues, from the origin of the concept to its "Maturation" to extracellular matrix. Application to ocular tissues. Contribution to the history of medical sciences]. / Les tissus conjonctifs, de l'origine du concept à sa « mutation ¼ en matrice extracellulaire. Application aux tissus oculaires. Contribution à l'histoire des sciences médicales.

The "Tissue" concept emerged apparently in the medical literature at about the French revolution, during the second half of the 18(th) century. It was found in the texts written by the physicians of Béarn and Montpellier, the Bordeu-s and also by the famous physician, Felix Vicq d'Azyr, the last attending physician of the queen Marie-Antoinette, "Bordeu et al. (1775) et Pouliquen (2009)". It was elaborated into a coherent doctrine somewhat later by Xavier Bichat, considered as the founder of modern pathological anatomy, Bichat. With the advent of histochemistry, from the beginning of the 20(th) century, several of the principal macromolecular components of connective tissues, collagens, elastin, "acid mucopolysaccharides" (later glycosaminoglycans and proteoglycans) and finally structural glycoproteins were characterized. These constituents of connective tissues were then designated as components of the extracellular matrix (ECM), closely associated to the cellular components of these tissues by adhesive (structural) glycoproteins as fibronectin, several others and cell receptors, "recognising" ECM-components as integrins, the elastin-receptor and others. This molecular arrangement fastens cells to the ECM-components they synthesize and mediates the exchange of informations between the cells to the ECM (inside-out) and also from the ECM-components to the cells (outside-in). This macromolecular arrangement is specific for each tissue as a result of the differentiation of their cellular components. It is also the basis and condition of the fulfillment of the specific functions of differentiated tissues. This is a short description of the passage of the "tissue" concept from its vague origin towards its precise identification at the cellular and molecular level up to the recognition of its functional importance and its establishment as an autonomous science. This can be considered as a new example of the importance of metaphors for the progress of science, Keller (1995).

Genetic, epigenetic and posttranslational mechanisms of aging.

Gerontological experimentation is and was always strongly influenced by "theories". The early decades of molecular genetics inspired deterministic thinking, based on the "Central Dogma" (DNA --> RNA --> Proteins). With the progress of detailed knowledge of gene-function a much more complicated picture emerged. Regulation of gene-expression turned out to be a highly complicated process. Experimental gerontology produced over the last decades several "paradigms" incompatible with simple genetic determinism. The increasing number of such detailed experimental "facts" revealed the importance of epigenetic factors and of posttranslational modifications in the age-dependent decline of physiological functions. We shall present in this review a short but critical analysis of genetic and epigenetic processes applied to the interpretation of the more and more precisely elucidated experimental paradigms of aging followed by some of the most relevant aging-mechanisms at the post-translational level, the posttranslational modifications of proteins such as the Maillard reaction, the proteolytic production of harmful peptides and the molecular mechanisms of the aging of elastin with the role of the age-dependent uncoupling of the elastin receptor, as well as the loss of several other receptors. We insist also on the well documented influence of posttranslational modifications on gene expression and on the role of non-coding RNA-s. Altogether, these data replace the previous simplistic concepts on gene action as related to aging by a much more complicated picture, where epigenetic and posttranslational processes together with environmentally influenced genetic pathways play key-roles in aging and strongly influence gene expression.

The Maillard reaction. From nutritional problems to preventive medicine.

The questions we were asked by Dr Edeas, president of the French Society of Antioxidants to discuss in this introductory lecture are the following: (a) the metabolism of glycation; (b) what are its consequences at the cellular level, and (c) their effect on health. As a recent and vast literature is available on these subjects, in the following we present a short survey of some basic data on the proposed subjects, insisting on our own experiments on the cytotoxicity of Maillard products and on a new approach to prevent the aggravation and acceleration of age-related diseases, essentially diabetes type II and its consequences on the cardiovascular system.

Receptors and aging: dedicated to the memory of Paul Ehrlich for the 100th anniversary of his Nobel Prize.

The initiation and evolution of the receptor concept and its application in pharmacology can be traced back to Paul Ehrlich's original experiments. Since several decades the receptor concept is in the foreground of cell biology and pharmacology. We present here a short reminder of Ehrlich's concepts on receptor action, its evolution and modifications as a result of increasing life expectancy of human societies. Results obtained by several teams on the age-dependent modifications of receptor function are reviewed with special emphasis on the age-dependent loss of receptors and of uncoupling of receptors from their intracellular transmission pathway. As a special example we summarize our results on the elastin receptor and its age-dependent modifications. These modifications result in the loss of the physiologically helpful functions mediated by this receptor, such as vasodilation by coupling with the inducible nitric oxide synthase (iNOS)-inhibition of cellular cholesterol synthesis and modulation of free radical production by inhibition of the guanine nucleotide binding protein (Gi protein)-mediated transmission pathway. Only the harmful effects such as free radical release and up-regulation of elastase production remain in "old" cells. The age-dependent modifications of receptor function play an important role in the increasing frequency and severity of age-related diseases such as athero-arteriosclerosis and emphysema as well as the loss of hormone- and drug actions. These processes and their inhibition or correction represent a new challenge for cellular pharmacology.

Physiology of skin aging.

Skin is the most voluminous organ of the body. It assumes several important physiological functions and represents also a "social interface" between an individual and other members of society. This is the main reason its age-dependent modifications are in the forefront of dermatological research and of the "anti-aging" cosmetic industry. Here we concentrate on some aspects only of skin aging, as far as the cellular and extracellular matrix components of skin are concerned. Most well studied mechanisms of skin aging can be situated at the postgenetic level, both epigenetic and post-translational mechanisms being involved. Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.

The metabolic syndrome and the Maillard reaction. An introduction.

With the rapid increase of life expectancy in western societies, appeared also a new phenomenon, obesity, which took during the recent decades pandemic dimensions. One of the consequences was the appearance of type II diabetes in much younger persons than before. The result of intensive research in this field over the last decades led, among other achievements to the identification of biological and molecular symptoms which together were reclassified as the "metabolic syndrome". Questionable as far as its originality is concerned, it did however good service to practitioners by formulating criteria for diagnostic and therapeutical purposes. Among the underlying biochemical mechanisms the Maillard reaction, the non enzymatic glycosylation of proteins and nucleotide bases followed by the formation of advanced glycation and products (AGE-s) plays an important role. Several recent experimental results confirm this statement, some of them are published in this issue. The reviews and original contributions form together an up to date report on this important pathology and support again the importance of posttranslational and environmental factors influencing gene expression and cellular functions.